Interferons (IFNs) are cytokines with diverse biological functions, including antitumor, immunomodulatory, antiviral and antiparasitic actions. At present, the IFN family includes more than 20 different proteins and is grouped into two types: Type I and Type II. Based on their genetic similarities and differences, the type I IFNs consist primarily of IFN-.alpha. an IFN-.beta.. The type II IFNs consist of IFN-.gamma..
IFNs act by binding to specific cell receptors, which are found on the surface of most cells, and causing the translocation to the nucleus of cytoplasmic transcription factors that enhance or suppress the expression of specific genes. The products of these interferon-stimulated genes are primarily polypeptides that act as mediators of the biological activities associated with the respective IFN.
In the IFN-.gamma. signal transduction (Jak/Stat) pathway, IFN-.gamma. binds to the extracellular heterodimeric receptor subunits IFN-.gamma.R1 and IFN-.gamma.R2, which are associated intracellularly with Janus kinase 1 (Jak 1) and Janus kinase 2 (Jak 2), respectively. The binding initiates phosphorylation of tyrosine residues in Jak 1, Jak 2, and the cytoplasmic tail of IFN-.gamma.R1. Each phosphorylated IFN-.gamma.R1 chain becomes a docking site for Stat 1 .alpha., a member of the family of signal transducers and activators of transcription. After docking at the receptor, Stat 1 .alpha. is phosphorylated by the Jaks and forms a homodimer known as IFN-.gamma. activation factor (GAF). GAF migrates to the nucleus where it binds the IFN-.gamma. activation sequence (GAS) elements present in the promotors of IFN-.gamma. inducible genes.
High affinity IFN receptors exist on most cells. IFN-.alpha. and IFN-.beta. share the same receptor complex. IFN-.gamma. binds to a separate receptor. Nonetheless, IFN-.alpha., IFN-.beta., and IFN-.gamma. all require the presence of the cytoplasmic protein tyrosine kinase Jak 1 to enhance the expression of specific genes. For example, IFN-.gamma. requires a functional JAK/STAT pathway to upregulate the class II transactivator, CIITA, and thereby induce MHC class II expression.
In certain instances, such as autoimmune diseases, IFN-.alpha., IFN-.beta., or IFN-.gamma. activation of interferon-stimulation genes can cause a deleterious inflammatory reaction in an individual. Accordingly, it is desirable to have tools and methods for blocking the signal transduction pathways employed by IFNs. It is especially desirable to have tools and methods for reducing levels of JAK 1.